Abstract
Influenza-associated pulmonary aspergillosis (IAPA) is a global recognized superinfection in critically ill influenza patients. Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is a newly approved anti-influenza therapeutic. Although the benefits as a treatment for influenza are clear, its efficacy against an influenza-A. fumigatus co-infection has yet to be determined. We investigated the therapeutic effect of baloxavir marboxil in a murine model for IAPA. Immunocompetent mice received intranasal instillation of influenza A followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Administration of baloxavir marboxil or sham was started at day 0, day 2 or day 4. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). In vivo imaging was supplemented with virological, mycological and biochemical endpoint investigations. We observed an improved body weight, survival and viral clearance in baloxavir marboxil treated mice. µCT showed less pulmonary lesions and bronchial dilation after influenza and after Aspergillus co-infection in a treatment-dependent pattern. Furthermore, baloxavir marboxil was associated with effective inhibition of fungal invasion. Hence, our results provide evidence that baloxavir marboxil mitigates severe influenza thereby decreasing the susceptibility to a lethal invasive Aspergillus superinfection.
Highlights
Over the past four decades, viral associated pulmonary aspergillosis (VAPA), such as influenza-associated pulmonary aspergillosis (IAPA) or more recently COVID-19-associated pulmonary aspergillosis (CAPA), have become new entities in the world as serious lifethreatening infectious diseases [1,2,3,4,5,6,7,8,9,10]
To assess the time-dependent treatment effect of baloxavir marboxil on the severity of influenza and subsequent susceptibility to invasive pulmonary aspergillosis (IPA) in this double-hit mouse model, we treated mice with baloxavir marboxil or phosphate-buffered saline (PBS) started at day 0, day 2 or day 4 up to day 7 (Figure 1A)
All baloxavir marboxil-treated mice experienced only a moderate body weight loss (Figure 1B) and less animals reached the humane endpoint at day 7 (Figure 1C) the earlier treatment was started
Summary
Over the past four decades, viral associated pulmonary aspergillosis (VAPA), such as influenza-associated pulmonary aspergillosis (IAPA) or more recently COVID-19-associated pulmonary aspergillosis (CAPA), have become new entities in the world as serious lifethreatening infectious diseases [1,2,3,4,5,6,7,8,9,10]. Ever since the flu pandemic of 2009, the neuraminidase inhibitor (NAI) oseltamivir has been used as standard-of-care treatment to suppress influenza. This drug prevents the release and spread of the influenza virus from the host cell by inhibiting the viral neuraminidase. Only limited inhibitory effects of oseltamivir on mammalian sialidases were reported [15], Dewi et al (2021) showed that oseltamivir influences the host response against A. fumigatus in vitro by inhibiting the endogenous neuraminidases resulting in an impaired capacity of human peripheral blood mononuclear cells (PBMCs) and murine splenocytes to kill Aspergillus [16]. In vivo, an increased susceptibility to IPA with higher fungal burden and mortality was found [16]
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